Summary/Abstract Hybrid coronary revascularization (HCR) is the intentional combination of minimally invasive surgical grafting of the left anterior descending artery (LAD) coronary artery using the left internal mammary artery (LIMA) with percutaneous coronary intervention (PCI) of non-LAD coronary stenosis. HCR procedures are being adopted by clinicians nationwide, in an effort to reduce morbidity, mortality, recovery time, repeat re-interventions, and the costs of revascularization for patients with multi-vessel coronary artery disease (CAD) involving the LAD and/or left main coronary arteries. To date, there has been no randomized controlled trial to establish whether HCR achieves these results, and increasing adoption of HCR is proceeding without a solid evidence base. The proposed trial is designed to fill this knowledge gap and provide an evidence base for clinical practice. We propose a pragmatic, large-scale clinical trial that evaluates the effectiveness and safety of HCR compared to multi-vessel PCI. The trial will enroll 2354 patients with multi-vessel CAD involving the LAD distribution and a clinical indication for revascularization, who are eligible for both HCR and multi-vessel PCI with drug eluting stents. The primary outcome will be occurrence of MACCE, defined as all-cause mortality, myocardial infarction, stroke, and repeat revascularization over a minimum of 5 year follow-up after randomization. A vanguard phase will be conducted over the first year of the trial to establish feasibility of enrollment and data completeness of centralized collection of MACCE events. The innovative design of the trial combines collection and adjudication of minimal trial-specific data with national registry data (STS and NCDR), resulting in a streamlined and very cost-effective trial. A previous NIH-funded observational study (RC1 HL100951-01, Principal Investigators, J. Puskas, D. Ascheim), informing the design of this trial, demonstrated that 10-15% of patients with CAD are anatomically eligible for HCR and confirmed that equipoise exists among cardiologists and surgeons to randomize such patients. To conduct this trial, we have assembled a Hybrid Trial Network of 49 selected clinical sites experienced in multi-vessel PCI, minimally invasive LIMA-LAD grafting, and HCR. Co-Investigators from cardiology and cardiac surgery have signed Letters of Collaboration from all sites. In the past two years the Hybrid Network sites have performed >6500 CABG procedures and approximately 15,000 multi-vessel PCI procedures for patients with suitable coronary anatomy, and, therefore, have a large volume of patients eligible for HCR. The results of the Hybrid Trial could fundamentally change management of patients with CAD, the number one cause of death in the United States. This trial, which will support numerous clinical centers across the country and the DCC and CCC, will provide evidence to guide and improve treatment decisions and optimize the utilization of health care resources for this growing patient population.